ABSTRACT
Background: Normal organ function is critically dependent on an intact three-dimensional architecture. Structural abnormalities induced by pathological situations instruct cells to behave abnormally and promoting disease progression oftentimes leading to organ failure. Current approaches do not allow for high-resolution (HR) threedimensional (3D) visualisation and analysis of human organ structure. Method(s): Here, we develop a method to perfuse human tissue segments to remove cells and study the 3D structural scaffold, which could be applied to any organ. Our approach enables HR-3D imaging of organ architecture, which we apply to study healthy and diseased human lung, specifically emphysema, usual interstitial pneumonia, pulmonary sarcoidosis, and COVID-19. Result(s): Our imaging reveals major structural abnormalities previously unseen by existing methodologies. Furthermore, we identify disease-specific patterns of structural remodelling using machine learning, including the altered spatial relationship between extracellular matrix (ECM) proteins collagen type IV, elastin and fibrillar collagen present across all diseases. Conclusion(s): Given the importance of organ structure on function, our approach opens the possibility to understand human physiology in a new way, which may assist in future disease diagnosis and explain the detrimental pulmonary effects of the diseases studied here.